tbuckley/cabot-search huggingface dataset:
Antiracist Research and Practice for Environmental Health: Implications for Community Engagement
Authors: Donele Wilkins, Amy J. Schulz
Journal: Environmental Health Perspectives (2023)

Background: Communities who experience disproportionate environmental exposures and associated adverse health outcomes have long been aware of, and worked to draw attention to, the role of racism in shaping those risks. A growing number of researchers are focusing on racism as a fundamental driver of racial inequities in environmental health. Importantly, several research and funding institutions have publicly committed to addressing structural racism within their organizations. These commitments highlight structural racism as a social determinant of health. They also invite reflection on antiracist approaches to community engagement in environmental health research. Objectives: We discuss strategies for taking more explicitly antiracist approaches to community engagement in environmental health research. Discussion: Antiracist (as opposed to nonracist, color-blind, or race-neutral) frameworks entail thinking or acting in ways that explicitly question, analyze, and challenge policies and practices that produce or sustain inequities between racial groups. Community engagement is not inherently antiracist. There are, however, opportunities for extending antiracist approaches when engaging communities who are disproportionately harmed by environmental exposures. Those opportunities include a) promoting leadership and decision-making power by representatives from harmed communities, b) centering community priorities in identifying new research areas, and c) translating research into action by applying knowledge from multiple sources to disrupt policies and practices that create and sustain environmental injustices. https://doi.org/10.1289/EHP11384
Ready‐To‐Use and Rapidly Biodegradable Magnesium Phosphate Bone Cement: In Vivo Evaluation in Sheep
Authors: Lena Schröter, Friederike Kaiser, Anna‐Lena Preißler, Philipp Wohlfahrt, Oliver Küppers, Uwe Gbureck, Anita Ignatius
Journal: Advanced Healthcare Materials (2023)

Abstract In clinical practice, hydroxyapatite (HA) cements for bone defect treatment are frequently prepared by mixing a powder component and a liquid component shortly before implantation in the operation theater, which is time‐consuming and error‐prone. In addition, HA cements are only slightly resorbed, that is, cement residues can still be found in the bone years after implantation. Here, these challenges are addressed by a prefabricated magnesium phosphate cement paste based on glycerol, which is ready‐to‐use and can be directly applied during surgery. By using a trimodal particle size distribution (PSD), the paste is readily injectable and exhibits a compressive strength of 9–14 MPa after setting. Struvite (MgNH 4 PO 4 ·6H 2 O), dittmarite (MgNH 4 PO 4 ·H 2 O), farringtonite (Mg 3 (PO 4 ) 2 ), and newberyite (MgHPO 4 ·3H 2 O) are the mineral phases present in the set cement. The paste developed here features a promising degradation of 37% after four months in an ovine implantation model, with 25% of the implant area being newly formed bone. It is concluded that the novel prefabricated paste improves application during surgery, has a suitable degradation rate, and supports bone regeneration.
Associations of Pregnancy Per- and Polyfluoroalkyl Substance Concentrations and Uterine Fibroid Changes across Pregnancy: NICHD Fetal Growth Studies – Singletons Cohort
Authors: Susanna D. Mitro, Rajeshwari Sundaram, Germaine M. Buck Louis, Shyamal Peddada, Zhen Chen, Kurunthachalam Kannan, Jessica L. Gleason, Cuilin Zhang, Katherine L. Grantz
Journal: Environmental Health Perspectives (2023)

Background: Fibroids (hormonally responsive benign tumors) often undergo volume changes in pregnancy. Because per- and polyfluoroalkyl substances (PFAS) disrupt hormonal signaling, they might affect fibroid growth. We assessed associations between PFAS and fibroid changes in pregnancy. Methods: We analyzed seven PFAS, including perfluorohexanesulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), in plasma collected at 10–13 wk gestation from 2,621 women in the NICHD Fetal Growth Studies – Singletons cohort (2009–2013). Sonographers recorded fibroid number and volume of the three largest fibroids during up to six timed ultrasounds. Generalized linear models assessed associations of baseline log2-transformed PFAS and fibroid number, volume, and presence, and weighted quantile sum regression evaluated the PFAS mixture. Generalized linear mixed models with random intercepts assessed associations of PFAS and longitudinal fibroid number and total volume. Volume analyses were stratified by total volume at first visualization [equivalent to a fibroid <1cm (small), 1 to<3cm (medium), or ≥3cm (large) in diameter]. Results: Fibroid prevalence was 9.4% (n=245 women). PFAS were not associated with changes in fibroid number, but were associated with volume trajectory, depending on baseline volume. Among women with small volume, PFAS were associated with fibroid growth: Each doubling in PFHxS and PFOS concentrations was associated with 3.6% [95% confidence interval (CI): 0.2, 7.0 and 5.2% (95% CI: −0.4, 11.1)] greater weekly fibroid growth, respectively. Among women with medium volume, PFAS were associated with shrinking: Doublings in PFOS, PFDA, and PFUnDA concentrations were associated with 1.9% (95% CI: 0.4, 3.3), 1.2% (95% CI: 0.1, 2.4), and 1.6% (95% CI: 0.4, 2.8) greater weekly fibroid volume reduction, respectively. Discussion: Certain PFAS were associated with fibroid growth among women with small fibroids and decreases among women with medium fibroids. PFAS were not associated with fibroid prevalence or number; therefore, PFAS may influence prevalent fibroids rather than initiating fibroid development. https://doi.org/10.1289/EHP11606
Association of Temperature Thresholds with Heat Illness– and Cardiorespiratory-Related Emergency Visits during Summer Months in Alaska
Authors: Micah B. Hahn, Grace Kuiper, Sheryl Magzamen
Journal: Environmental Health Perspectives (2023)

Background: Recent record-breaking hot temperatures in Alaska have raised concerns about the potential human health implications of heat exposure among this unacclimated population. Objectives: We estimated cardiorespiratory morbidity associated with days above summer (June–August) heat index (HI, apparent temperature) thresholds in three major population centers (Anchorage, Fairbanks, and the Matanuska-Susitna Valley) for the years 2015–2019. Methods: We implemented time-stratified case–crossover analyses of emergency department (ED) visits for International Classification of Diseases, 10th Revision codes indicative of heat illness and major cardiorespiratory diagnostic codes using data from the Alaska Health Facilities Data Reporting Program. Using conditional logistic regression models, we tested maximum hourly HI temperature thresholds between 21.1°C (70°F) and 30°C (86°F) for a single day, 2 consecutive days, and the absolute number of previous consecutive days above the threshold, adjusting for the daily average concentration of particulate matter ≤2.5μg. Results: There were increased odds of ED visits for heat illness above a HI threshold as low as 21.1°C (70°F) [odds ratio (OR)=13.84; 95% confidence interval (CI): 4.05, 47.29], and this increased risk continued for up to 4 d (OR=2.43; 95% CI: 1.15, 5.10). Asthma and pneumonia were the only respiratory outcomes positively associated with the HI: ED visits for both were highest the day after a heat event (Asthma: HI&gt;27°C(80°F) OR=1.18; 95% CI: 1.00, 1.39; Pneumonia: HI&gt;28°C(82°F) OR=1.40; 95% CI: 1.06, 1.84). There was a decreased odds of bronchitis-related ED visits when the HI was above thresholds of 21.1–28°C (70–82°F) across all lag days. We found stronger effects for ischemia and myocardial infarction (MI) than for respiratory outcomes. Multiple days of warm weather were associated with an increased risk of health impacts. For each additional preceding day above a HI of 22°C (72°F), the odds of ED visits related to ischemia increased 6% (95% CI: 1%, 12%); for each additional preceding day above a HI of 21.1°C (70°F), the odds of ED visits related to MI increased 7% (95% CI: 1%, 14%). Discussion: This study demonstrates the importance of planning for extreme heat events and developing local guidance for heat warnings, even in areas with historically mild summertime climates. https://doi.org/10.1289/EHP11363
The immune response in tubercular uveitis and its implications for treatment: From anti-tubercular treatment to host-directed therapies
Authors: Ikhwanuliman Putera, Benjamin Schrijver, Josianne C.E.M. ten Berge, Vishali Gupta, Rina La Distia Nora, Rupesh Agrawal, P. Martin van Hagen, Saskia M. Rombach, Willem A. Dik
Journal: Progress in Retinal and Eye Research (2023)

Tubercular uveitis (TB-uveitis) remains a conundrum in the uveitis field, which is mainly related to the diverse clinical phenotypes of TB-uveitis. Moreover, it remains difficult to differentiate whether Mycobacterium tuberculosis (Mtb) is present in the ocular tissues, elicits a heightened immune response without Mtb invasion in ocular tissues, or even induces an anti-retinal autoimmune response. Gaps in the immuno-pathological knowledge of TB-uveitis likely delay timely diagnosis and appropriate management. In the last decade, the immunopathophysiology of TB-uveitis and its clinical management, including experts' consensus to treat or not to treat certain conditions with anti-tubercular treatment (ATT), have been extensively investigated. In the meantime, research on TB treatment, in general, is shifting more toward host-directed therapies (HDT). Given the complexities of the host-Mtb interaction, enhancement of the host immune response is expected to boost the effectiveness of ATT and help overcome the rising burden of drug-resistant Mtb strains in the population. This review will summarize the current knowledge on the immunopathophysiology of TB-uveitis and recent advances in treatment modalities and outcomes of TB-uveitis, capturing results gathered from high- and low-burden TB countries with ATT as the mainstay of treatment. Moreover, we outline the recent progress of HDT development in the pulmonary TB field and discuss the possibility of its applicability to TB-uveitis. The concept of HDT might help direct future development of efficacious therapy for TB-uveitis, although more in-depth research on the immunoregulation of this disease is still necessary.
A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial
Authors: Anne Hoffmann, Anat Yaskolka Meir, Tobias Hagemann, Paul Czechowski, Luise Müller, Beatrice Engelmann, Sven-Bastiaan Haange, Ulrike Rolle-Kampczyk, Gal Tsaban, Hila Zelicha, Ehud Rinott, Alon Kaplan, Ilan Shelef, Michael Stumvoll, Matthias Blüher, Liming Liang, Uta Ceglarek, Berend Isermann, Martin von Bergen, Peter Kovacs, Maria Keller, Iris Shai
Journal: Metabolism (2023)

<h2>Abstract</h2><h3>Background</h3> The capacity of a polyphenol-enriched diet to modulate the epigenome in vivo is partly unknown. Given the beneficial metabolic effects of a Mediterranean (MED) diet enriched in polyphenols and reduced in red/processed meat (green-MED), as previously been proven by the 18-month DIRECT PLUS randomized controlled trial, we analyzed the effects of the green-MED diet on methylome and transcriptome levels to highlight molecular mechanisms underlying the observed metabolic improvements. <h3>Methods</h3> Our study included 260 participants (baseline BMI = 31.2 kg/m<sup>2</sup>, age = 5 years) of the DIRECT PLUS trial, initially randomized to one of the intervention arms: A. healthy dietary guidelines (HDG), B. MED (440 mg polyphenols additionally provided by walnuts), C. green-MED (1240 mg polyphenols additionally provided by walnuts, green tea, and Mankai: green duckweed shake). Blood methylome and transcriptome of all study subjects were analyzed at baseline and after completing the 18-month intervention using Illumina EPIC and RNA sequencing technologies. <h3>Results</h3> A total of 1573 differentially methylated regions (DMRs; false discovery rate (FDR) < 5 %) were found in the green-MED compared to the MED (177) and HDG (377) diet participants. This corresponded to 1753 differentially expressed genes (DEGs; FDR < 5 %) in the green-MED intervention compared to MED (7) and HDG (738). Consistently, the highest number (6 %) of epigenetic modulating genes was transcriptionally changed in subjects participating in the green-MED intervention. Weighted cluster network analysis relating transcriptional and phenotype changes among participants subjected to the green-MED intervention identified candidate genes associated with serum-folic acid change (all <i>P</i> < 1 × 10<sup>−3</sup>) and highlighted one module including the <i>KIR3DS1</i> locus, being negatively associated with the polyphenol changes (e.g. <i>P</i> < 1 × 10<sup>−4</sup>), but positively associated with the MRI-assessed superficial subcutaneous adipose area-, weight- and waist circumference- 18-month change (all <i>P</i> < 0.05). Among others, this module included the DMR gene <i>Cystathionine Beta-Synthase</i>, playing a major role in homocysteine reduction. <h3>Conclusions</h3> The green-MED high polyphenol diet, rich in green tea and Mankai, renders a high capacity to regulate an individual's epigenome. Our findings suggest epigenetic key drivers such as folate and green diet marker to mediate this capacity and indicate a direct effect of dietary polyphenols on the one‑carbon metabolism.
Relationship between Climate Variables and Dengue Incidence in Argentina
Authors: María S. López, Andre A. Gómez, Gabriela V. Müller, Elisabet Walker, Michael A. Robert, Elizabet L. Estallo
Journal: Environmental Health Perspectives (2023)

Background: Climate change is an important driver of the increased spread of dengue from tropical and subtropical regions to temperate areas around the world. Climate variables such as temperature and precipitation influence the dengue vector’s biology, physiology, abundance, and life cycle. Thus, an analysis is needed of changes in climate change and their possible relationships with dengue incidence and the growing occurrence of epidemics recorded in recent decades. Objectives: This study aimed to assess the increasing incidence of dengue driven by climate change at the southern limits of dengue virus transmission in South America. Methods: We analyzed the evolution of climatological, epidemiological, and biological variables by comparing a period of time without the presence of dengue cases (1976–1997) to a more recent period of time in which dengue cases and important outbreaks occurred (1998–2020). In our analysis, we consider climate variables associated with temperature and precipitation, epidemiological variables such as the number of reported dengue cases and incidence of dengue, and biological variables such as the optimal temperature ranges for transmission of dengue vector. Results: The presence of dengue cases and epidemic outbreaks are observed to be consistent with positive trends in temperature and anomalies from long-term means. Dengue cases do not seem to be associated with precipitation trends and anomalies. The number of days with optimal temperatures for dengue transmission increased from the period without dengue cases to the period with occurrences of dengue cases. The number of months with optimal transmission temperatures also increased between periods but to a lesser extent. Conclusions: The higher incidence of dengue virus and its expansion to different regions of Argentina seem to be associated with temperature increases in the country during the past two decades. The active surveillance of both the vector and associated arboviruses, together with continued meteorological data collection, will facilitate the assessment and prediction of future epidemics that use trends in the accelerated changes in climate. Such surveillance should go hand in hand with efforts to improve the understanding of the mechanisms driving the geographic expansion of dengue and other arboviruses beyond the current limits. https://doi.org/10.1289/EHP11616
Durability and determinants of anti-SARS-CoV-2 spike antibodies following the second and third doses of mRNA COVID-19 vaccine
Authors: Shohei Yamamoto, Yusuke Oshiro, Natsumi Inamura, Takashi Nemoto, Kumi Horii, Kaori Okudera, Maki Konishi, Mitsuru Ozeki, Tetsuya Mizoue, Haruhito Sugiyama, Nobuyoshi Aoyanagi, Wataru Sugiura, Norio Ohmagari
Journal: Clinical Microbiology and Infection (2023)

To examine the differences in durability and its determinants of humoral immunity following 2- and 3-dose COVID-19 vaccination.Throughout the pandemic, we evaluated the anti-spike IgG antibody titers of 2- and 3-dose mRNA vaccine recipients over time among the staff of a medical and research center in Tokyo. Linear mixed models were used to estimate trajectories of antibody titers from 14 to 180 days after the last immune-conferred event (vaccination or infection) and compare antibody waning rates across prior infection and vaccination status, and across background factors in infection-naïve participants.A total of 6901 measurements from 2964 participants (median age, 35 years; 30% male) were analyzed. Antibody waning rate (percentage per 30 days [95% CI]) was slower after 3 doses (25% [23-26]) than 2 doses (36% [35-37]). Participants with hybrid immunity (vaccination and infection) had further slower waning rates: 2-dose plus infection (16% [9-22]); 3-dose plus infection (21% [17-25]). Older age, male sex, obesity, coexisting diseases, immunosuppressant use, smoking, and alcohol drinking were associated with lower antibody titers, whereas these associations disappeared after 3 doses, except for sex (lower in female participants) and immunosuppressant use. Antibody waned slightly faster in older participants, females, and alcohol drinkers after 2 doses, whereas it did not differ after 3 doses across except sex.The 3-dose mRNA vaccine conferred higher durable antibody titers, and previous infection modestly enhanced its durability. The antibody levels at a given time point and waning speed after 2 doses differed across background factors; however, these differences mostly diminished after 3 doses.
Conditioning of the immune system by the microbiome
Authors: Daniel B. Graham, Ramnik J. Xavier
Journal: Trends in Immunology (2023)

The human intestinal microbiome has coevolved with its host to establish a stable homeostatic relationship with hallmark features of mutualistic symbioses, yet the mechanistic underpinnings of host-microbiome interactions are incompletely understood. Thus, it is an opportune time to conceive a common framework for microbiome-mediated regulation of immune function. We propose the term conditioned immunity to describe the multifaceted mechanisms by which the microbiome modulates immunity. In this regard, microbial colonization is a conditioning exposure that has durable effects on immune function through the action of secondary metabolites, foreign molecular patterns, and antigens. Here, we discuss how spatial niches impact host exposure to microbial products at the level of dose and timing, which elicit diverse conditioned responses.
Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors
Authors: Caroline Marty, Cécile Saint-Martin, Christian Pecquet, Sarah Grosjean, Joseph Saliba, Céline Mouton, Emilie Leroy, Ashot S. Harutyunyan, Jean-François Abgrall, Rémi Favier, Aurélie Toussaint, Eric Solary, Robert Kralovics, Stefan N. Constantinescu, Albert Najman, William Vainchenker, Isabelle Plo, Christine Bellanné-Chantelot
Journal: Blood (2014)
Understanding and targeting resistance mechanisms in cancer
Authors: Zi‐Ning Lei, Qin Tian, Qiu‐Xu Teng, John N. D. Wurpel, Leli Zeng, Yihang Pan, Zhe‐Sheng Chen
Journal: MedComm (2023)

Resistance to cancer therapies has been a commonly observed phenomenon in clinical practice, which is one of the major causes of treatment failure and poor patient survival. The reduced responsiveness of cancer cells is a multifaceted phenomenon that can arise from genetic, epigenetic, and microenvironmental factors. Various mechanisms have been discovered and extensively studied, including drug inactivation, reduced intracellular drug accumulation by reduced uptake or increased efflux, drug target alteration, activation of compensatory pathways for cell survival, regulation of DNA repair and cell death, tumor plasticity, and the regulation from tumor microenvironments (TMEs). To overcome cancer resistance, a variety of strategies have been proposed, which are designed to enhance the effectiveness of cancer treatment or reduce drug resistance. These include identifying biomarkers that can predict drug response and resistance, identifying new targets, developing new targeted drugs, combination therapies targeting multiple signaling pathways, and modulating the TME. The present article focuses on the different mechanisms of drug resistance in cancer and the corresponding tackling approaches with recent updates. Perspectives on polytherapy targeting multiple resistance mechanisms, novel nanoparticle delivery systems, and advanced drug design tools for overcoming resistance are also reviewed.
Metabolomics in drug research and development: The recent advances in technologies and applications
Authors: Huanhuan Pang, Zeping Hu
Journal: Acta Pharmaceutica Sinica B (2023)

Emerging evidence has demonstrated the vital role of metabolism in various diseases or disorders. Metabolomics provides a comprehensive understanding of metabolism in biological systems. With advanced analytical techniques, metabolomics exhibits unprecedented significant value in basic drug research, including understanding disease mechanisms, identifying drug targets, and elucidating the mode of action of drugs. More importantly, metabolomics greatly accelerates the drug development process by predicting pharmacokinetics, pharmacodynamics, and drug response. In addition, metabolomics facilitates the exploration of drug repurposing and drug-drug interactions, as well as the development of personalized treatment strategies. Here, we briefly review the recent advances in technologies in metabolomics and update our knowledge of the applications of metabolomics in drug research and development.
A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies
Authors: Chiara Tomasoni, Alice Pievani, Benedetta Rambaldi, Andrea Biondi, Marta Serafini
Journal: HemaSphere (2023)

Until a few years ago, the onset of acute myeloid leukemia (AML) was entirely ascribed to genetic lesions in hematopoietic stem cells. These mutations generate leukemic stem cells, which are known to be the main ones responsible for chemoresistance and relapse. However, in the last years, increasing evidence demonstrated that dynamic interplay between leukemic cells and bone marrow (BM) niche is of paramount relevance in the pathogenesis of myeloid malignancies, including AML. Specifically, BM stromal niche components, such as mesenchymal stromal cells (MSCs) and their osteoblastic cell derivatives, play a key role not only in supporting normal hematopoiesis but also in the manifestation and progression of myeloid malignancies. Here, we reviewed recent clinical and experimental findings about how genetic and functional alterations in MSCs and osteolineage progeny can contribute to leukemogenesis and how leukemic cells in turn generate a corrupted niche able to support myeloid neoplasms. Moreover, we discussed how the newest single-cell technologies may help dissect the interactions between BM stromal cells and malignant hematopoiesis. The deep comprehension of the tangled relationship between stroma and AML blasts and their modulation during disease progression may have a valuable impact on the development of new microenvironment-directed therapeutic strategies, potentially useful for a wide cohort of patients.